The metabolic syndrome is increasingly prevalent in our society and represents a major risk for[unreadable] vascular disease. This syndrome is characterized by central obesity, insulin resistance, fasting and[unreadable] post-prandial atherogenic dyslipidemia as well as a chronic pro-inflammatory state. Thus, chronic[unreadable] activation of innate immunity and postprandial stress converge on the vasculature in the metabolic[unreadable] syndrome.[unreadable] We use low-level human endotoxemia as a model to examine the impact of adiposity and metabolic[unreadable] syndrome on vascular injury and atherogenic signaling in vivo. We have found that this model[unreadable] provides novel mechanistic insight into human pathophysiology in the metabolic syndrome. In this[unreadable] SCCOR project we propose to extend this work by; (Specific Aim 1) performing a placebo controlled[unreadable] trial of peroxisome proliferator-activated receptor alpha (Fenofibrate) and gamma (Rosiglitazone) agonists and[unreadable] Niacin (collaboration with Project by Rader); (Specific Aim 2) use of placebo-controlled acute highfat[unreadable] meal provocation; and (Specific Aim 3) performing an evoked-phenotype pharmacogenetic study[unreadable] on the endotoxin-mediated vascular injury response.[unreadable] In specific hypothesis-driven studies, we will determine the impact of drugs, diet and genes on[unreadable] endotoxin-related vascular injury pathways including; (a) cytokines and inflammatory molecules, (b)[unreadable] cyclooxygenases (COXs) and vasoactive prostaglandins (PGs), particularly PGD2 (collaboration[unreadable] with Project by Fitzgerald), (c) oxidant stress (utilize the Biomarker Core (Blair), and (d) vasoactive[unreadable] adipokines. Drug, diet and candidate gene related changes in leukocyte, monocyte and adipose[unreadable] gene expression will be integrated with plasma and urinary biomarker responses and will serve to[unreadable] provide mechanistic insights that will complement cell and animal model studies across our SCCOR[unreadable] application. Metabolic syndrome represents our major clinical focus because of the interplay of[unreadable] metabolic and inflammatory signals in the promotion of vascular injury and atherosclerosis in this[unreadable] setting.